Abstract
Sodium‐dependent nucleobase transporter 1 (SNBT1) is a nucleobase‐specific transporter identified in our recent study. In an attempt to search for its potential substrates other than nucleobases in this study, we could successfully find urate, a metabolic derivative of purine nucleobases, as a novel substrate, as indicated by its specific Na+‐dependent and saturable transport, with a Michaelis constant of 433 μmol/L, by rat SNBT1 (rSNBT1) stably expressed in Madin‐Darby canine kidney II cells. However, urate uptake was observed only barely in the everted tissue sacs of the rat small intestine, in which rSNBT1 operates for nucleobase uptake. These findings suggested that urate undergoes a futile cycle, in which urate transported into epithelial cells is immediately effluxed back by urate efflux transporters, in the small intestine. In subsequent attempts to examine that possibility, such a futile urate cycle was demonstrated in the human embryonic kidney 293 cell line as a model cell system, where urate uptake induced by transiently introduced rSNBT1 was extensively reduced by the co‐introduction of rat breast cancer resistance protein (rBCRP), a urate efflux transporter present in the small intestine. However, urate uptake was not raised in the presence of Ko143, a BCRP inhibitor, in the everted intestinal tissue sacs, suggesting that some other transporter might also be involved in urate efflux. The newly found urate transport function of SNBT1, together with the suggested futile urate cycle in the small intestine, should be of interest for its evolutional and biological implications, although SNBT1 is genetically deficient in humans.
Highlights
Urate is the end product of purine nucleobase metabolism in humans and known to be mainly eliminated by renal excretion (Bass et al 1950; Wu et al 1992; Oda et al 2002), in which it undergoes reabsorption as well as secretion in renal tubules after glomerular filtration
We examined the urate transport capability of human urate transporter 1 (URAT1) (Enomoto et al 2002; Ichida et al 2004; Endou and Anzai 2008), organic anion transporter 1 (OAT1) (Sekine et al 1997; Ichida et al 2003), and OAT3 (Cha et al 2001; Bakhiya et al 2003), which are known as major urate transporters, for comparison
The results suggest that rat SNBT1 (rSNBT1) is more efficient for urate transport than those urate transporters
Summary
Urate is the end product of purine nucleobase metabolism in humans and known to be mainly eliminated by renal excretion (Bass et al 1950; Wu et al 1992; Oda et al 2002), in which it undergoes reabsorption as well as secretion in renal tubules after glomerular filtration. It is known that urate undergoes tubular reabsorption, in which mainly involved are urate transporter 1 (URAT1)/SLC22A12 (Enomoto et al 2002; Hosoyamada et al 2004; Ichida et al 2004; Endou and Anzai 2008) for brush border uptake and glucose transporter 9 (GLUT9)/SLC2A9 (Caulfield et al 2008; Bibert et al 2009; Preitner et al 2009) for subsequent basolateral efflux. The renal disposition of urate is delicately regulated by its secretion and reabsorption that involve various transporters in renal tubules (Hediger et al 2005).
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